Photomicrographs of the striatum showing ( A ) normal neuron density (neurons indicated by arrows) in an age-matched control and ( B ) severe loss of neurons in the same area of GA-1 Case 5. (H&E stained sections, 40 3 objective magnification, bar = 20 m m). 

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... but failed to thrive and had multiple respiratory infections. At 15 months, he was unable to sit but had some head control and visual interaction. During a febrile illness at 18 months, he stopped breathing. Autopsy revealed laryngitis and dehydration. His head circumference had been on the 52 percentile at birth, 89 percentile at 3 months, 63 percentile at 8 months and was on the 50 percentile at the time of death. The brain exhibited mild widening of temporal and frontal sulci, and pronounced widening of the Sylvian fissures. No histological abnormalities were apparent in the cerebral cortex of the temporal lobe tips or frontal lobes. The caudate nuclei were small, yellowish and firm. There was symmetric lateral ventricle enlargement ( Fig. 1). The head of the caudate and the putamen exhibited severe neuronal loss with pronounced reactive astrocytes. Only rare reactive microglia were identified. The tail of the caudate adjacent to the hippocampus appeared normal. The cerebral white matter exhibited no vacuoles, no damaged axons were identified using amyloid precursor protein immunohistochemistry, and no myelin debris could be demonstrated with the Marchi method. Rare vacuoles were present in the central tegmental tract at the level of the midbrain. This female born by forceps delivery at 37 weeks gestation, in 1983, had generalized hypotonia in infancy. She is Case 1 in pedigree A described in the clinical report of this cohort (Haworth et al ., 1991). At 6 months of age, she developed seizures and choreoathetoid movements. Thereafter she developed severe spastic quadriparesis. She was unable to walk and developed severe scoliosis. A CT scan at 5 years showed enlarged frontal horns and slightly wide Sylvian fissures. She died of acute pneumonia at age 7 years. Her head circumference had been on the 25 percentile at birth, 52 percentile at 6 months, 3 percentile at 19 months and 25 percentile at the time of death. Her brain exhibited mild gyral flattening, slightly enlarged ventricles and severe striatal atrophy. The caudate and putamen had a near complete loss of medium size neurons (Fig. 2) and some GFAP immunoreactive astrocytes; the nucleus accumbens was spared. Scattered hypertrophic astrocytes and very rare HLA-DR immunoreactive microglia were present in the internal capsule— although there were no vacuoles. There were small foci of spongiform change in the frontal and insular cortex. This male born at 40 weeks gestation, in 1953, was apparently slow to breathe. He had three siblings that died in infancy from pneumonia. He is Case 14 in pedigree E described in the clinical report of this cohort (Haworth et al ., 1991). At 12 months of age, he developed a high fever and was admitted to hospital with dystonia. At 6 years, he was documented to have severe flexor spasticity of the arms and legs, choreoathetoid movements and oral dyskinesia. Seizures were reported only early in life. He resided in a nursing care facility for his entire life. At no time was brain imaging conducted and head circumference information was not available. He required many hospitalizations for aspiration pneumonia. On one such admission at age 40 years, the treatment was complicated by pseudomembranous colitis from which he died. His brain had a normal external appearance. The frontal horns of the lateral ventricles were moder- ately enlarged. There was marked atrophy of the caudate and putamen with neuronal loss and abundant corpora amylacea. There was no significant immunoreactivity for GFAP or HLA-DR. The anterior nucleus accumbens was spared. The white matter of the cerebrum and brainstem was well myelinated and no vacuoles were identified. Subtle chronic astrogliosis, demonstrable with modified phosphotungstic acid haematoxylin (PTAH) stain, was evident in the inferior olivary nuclei but there was no obvious neuron loss. Very rare empty basket cells were present in the cerebellum, suggestive of mild Purkinje cell loss. Frontal cortex tissue was examined in all cases, none provided evidence of obvious cell loss or reactive changes. Quantitative comparison of the striatum in GA 1 cases and controls showed statistically significant ( P < 0.05) loss ...